Role of interleukin‐15 in cardiovascular diseases

Abstract Interleukin (IL)‐15 is a recently identified cytokine, which belongs to the interleukin‐2(IL‐2) family, and plays an important role in innate and adaptive immunoreaction. Given the fact that the structure of IL‐15 is partially similar to IL‐2, they share some common biological effects, including immunoregulation. IL‐2 was proven to protect cardiac function in mouse myocardial infarction models. Cardiovascular diseases (CVDs) dominate the cause of mortality worldwide. Besides atherosclerosis, inflammation is also widely involved in the pathogenesis of many CVDs including hypertension, heart failure (HF) and aneurysm. IL‐15, as a pro‐inflammatory cytokine, is up‐regulated in some cardiovascular diseases, such as myocardial infarction and atherosclerosis. The current understanding of IL‐15, including its signal pathway and cellular function, was described. Furthermore, IL‐15 has a protective effect in myocardial infarction and myocarditis by decreasing cardiomyocyte death and improving heart function. The inhibited effect of IL‐15 in ductus arteriosus (DA) should be focused on. IL‐15 promoted atherogenesis. IL‐15 may be a good target in treatment of cardiovascular diabetology. Finally, future research direction of IL‐15 deserves attention. Since IL‐15 plays several roles in CVDs, understanding the role of the IL‐15/IL‐15R system may provide a scientific basis for the development of new approaches that use IL‐15 for the treatment of CVDs.


| Association between CVDs and Inflammation
CVDs are the world's leading cause of mortality. Various risk factors entailing elevated cholesterol levels, insulin resistance, diabetes and obesity are involved in the initiation and development of atherosclerotic lesions. 6 Heart failure (HF) may be the terminal stage of various cardiovascular diseases, as one of major obstacles to CVDs management in the 21st century. Over the past few years, the prevalence of HF has been on the rise, mainly due to the ageing population trend, and an increase in patients with CVDs surviving with the help of modern interventional strategies. 7 In Abeywardena et al 2009, the data gathered about CVDs were shown to demonstrate that systemic inflammation is frequently found in CVDs. Inflammation leads to elevated levels of the pro-inflammatory cytokine that disrupt the systematic balance, suggesting that inflammation may lead to the damage and dysfunction of the cardiovascular system, such as interleukin-6(IL-6) and interleukin-1β(IL-1β). Acute myocardial infarction has been reported to be associated with the production of pro-inflammatory cytokines with high concentrations of IL-1β, tumour necrosis factor(TNF-α) and IL-6. 8 Biological activities of inflammatory factors in CVDs are effective in the plaque formation and rupture, endothelial dysfunction, and eventually, coronary thrombosis. 9 ILs are a family of cytokines that exert their effects via gene activation involved in differentiation, cellular stimulation, growth, cellular effector function and functional cell surface receptor expression. 10

| IL-15, a member of IL-2 family, is a crucial mediator of inflammation
Firstly, IL-15 was discovered in the field of haematology as a member of the immunoregulatory cytokines family with multiple functions, including dictating T-cell response, regulating tissue repair and B-cell homing, modulating inflammation and activating NK cells. 11 Subsequently, it was found to be expressed by monocytes, macrophages and other cell types involved in immune regulation comprising both innate and adaptive immune responses. 5 IL-2 and IL-15 bind to a common heterodimeric receptor composed of the IL-2/15Rβ (CD122) and common γ (gc or CD132) chains for signal transmission.

IL-2Rα
IL-2 II IL-15Rα IL-15 I is located on the human chromosome 4q31 and the central region of mouse chromosome 8. 14 Both humans and laboratory mice exhibit detectable levels of IL-15 in the circulation, suggesting that it can exert endocrine effects on the cell types which do not express the cytokine itself. 15 IL-15Rα consists of a 173-amino acid (aa) extracellular domain, a single 21-aa membrane-spanning region and a 37-aa cytoplasmic domain. This is structurally similar to IL-2Rα with a conserved extracellular protein-binding Sushi domain. Also, the intron-exon organization of the IL-15Rα gene is similar to that of IL-2Rα. Despite these similarities, IL-15Rα shares little sequence homology to IL-2Rα. 16   is widely expressed in humans and mice independently of IL-2R/IL-15Rβ-γ chain. It binds to IL-15 with a high affinity and retains IL-15 on the cell surface. IL-15 bound to IL-15Rα can also recycle through endosomal vesicles for many days (endosomal recycling), resulting in the persistence of membrane-bound IL-15. 17 Up-regulation of IL-15 and IL-15Rα is found during inflammatory responses. IL-15 is not a simple growth factor, but also a multifaceted regulator. In addition to it, the signalling pathways of IL-15 are highly connected with various cell types, which are mediated through numerous pathways and signalling molecules ( Figure 2). 18 Accumulating evidence suggests that skeletal muscles are also a major source of this cytokine. [19][20][21] The expression of IL-15 and IL-15Rα has been detected in many cell types and is summarized in Table 1 in the vulnerable atherosclerotic plaques, and serum IL-15 concentration is significantly higher in patients with CAD or peripheral artery disease than in healthy individuals. 6,31 In the light of these findings, it is reasonable to speculate that IL-15 might also play a role in the cardiovascular system. The correlation between IL-15 levels and numerous CVDs is shown in Table 2.  Significantly higher (serum levels) 6 Myocardial infarction (4-6h) after onset of ischaemia: +++ >6-8h from the onset of ischaemic symptoms and signs: + (frozen cardiac tissue's WB) 3 Atherosclerosis hypercholesterolemia Significantly higher (spleen and blood) 34 CCAD compared with non-CAD IL-15 and IL-15Rα are significantly higher (Plasma levels)

| Role of IL-15 in myocardial infarction
Coronary artery disease may lead to myocardial infarction (MI), a leading cause of death worldwide. 42

IL-15
Glucose take While the levels of IL-15, high sensitive C-reactive protein(hs-CRP), blood urea nitrogen(BUN), total cholesterol(TC), triglyceride(TG), and high-density lipoprotein cholesterol (HDL-C)and body mass index(BMI)were associated with CHD in univariate analysis, only IL-15 and hs-CRP levels were associated with CADs in multivariate logistic regression analysis. 45

| IL-15 acts as a biomarker of atrial fibrillation (AF)
Chronic inflammation due to autoimmune diseases is associated with a high rate of supraventricular and ventricular arrhythmias.

| Role of IL-15 in ductus arteriosus (DA)
DA is a foetal arterial connection between the main pulmonary artery and the descending aorta that closes immediately after birth. During

| Role of IL-15 in glycometabolism
IL-15 is not only a pro-inflammatory cytokine but also a 'myokine'.
Myokine is a kind of cytokine secreted by skeletal muscle, which has been identified as an endocrine organ. Besides IL-15, there are many myokines, such as IL-6, irisin and decorin. 51 Skeletal muscle contractile activity increases the production of myokines.
And these myokines can stimulate glucose transport. 52

| D ISCUSS I ON
It is not hard to draw a conclusion that IL-15 benefits cardiovascular system. Some phenomena about IL-15 have been found, but the mechanism needs further study. IL-15 has a positive effect on CVB3-induced murine myocarditis and promotes survival in cardiomyocytes. 21 Moreover, administration of IL-15 could improve heart function of C57/B6 mouse after myocardial infarction by reducing cardiomyocyte death. 43 It is interesting that the IL-15 level increases in patients with CVDs. Plasma levels of IL-15 and IL-15Rα were higher in CAD than non-CAD patients. 3,5,6,34 It also aggravates the development of atherosclerotic lesions in LDL-R-deficient mice. 35 But IL-15 inhibits the deposition of lipids in cultured adipocytes and decreases the deposition of adipose tissues in laboratory rodents. 37,41 The roles of IL-15 in hyperlipidaemia and atherosclerosis are controversial, and the underlying mechanism needs to be further explored. The cytokine is also deemed as a marker of refractory atrial fibrillation. 46 Although the potential protective role of  has been demonstrated in numerous in vitro and in vivo models of cardiovascular diseases, further studies are necessary to confirm the accurate mechanism and the most effective administration of IL-15 activators and inhibitors in these diseases. The evidence so far suggests that the association between signalling pathways and IL-15 in the cardiovascular system involves JAK/STAT and SMAD2/3 signalling; however, further research is needed. 33,34 IL-15 regulated glucose metabolism and may be a good target in treatment of cardiovascular diabetology. 62 Since IL-15 plays several roles in CVDs, understanding the role of the IL-15/IL-15R system may provide a scientific basis for the development of new approaches that use IL-15 for the treatment of CVDs.

ACK N OWLED G EM ENTS
The present study was supported by the National Natural Science Foundation of China (grant no. 81570322 and no.81100141).

CO N FLI C T O F I NTE R E S T
The authors declare that they have no competing interests.

AUTH O R CO NTR I B UTI O N
Lei Guo wrote the paper and drew the graphic, and Ming-fei Liu analysed the data and wrote the paper. Ji-niu Huang collected the literature. Jia-min Li analysed the data. Jun Jiang designed the research and drew the graphic. Jian-an Wang designed the research and drew.
All authors read and approved the final manuscript.

DATA AVA I L A B I L I T Y S TAT E M E N T
The NCBI database accession number for the protein profile data of IL-15 and IL-2 reported in this article is (PBD ID:1Z92, PBD ID:2Z3R).